The retina of the eye contains the cones and rods that detect light. In the center of the retina is the macula lutea, which is about ⅓ to ½ cm in diameter. The macula provides detailed vision, particularly in the center (the fovea), because the cones are higher in density. Blood vessels, ganglion cells, inner nuclear layer and cells, and the plexiform layers are all displaced to one side (rather than resting above the cones), thereby allowing light a more direct path to the cones.
Under the retina are the choroid, comprising a collection of blood vessels embedded within a fibrous tissue, and the deeply pigmented epithelium, which overlays the choroid layer. The choroidal blood vessels provide nutrition to the retina (particularly its visual cells).
There are a variety of retinal disorders for which there is currently no treatment or for which the current treatment is not optimal. Retinal disorders such as uveitis (an inflammation of the uveal tract: iris, ciliary body, and choroid), macular degeneration, macular edema, proliferative diabetic retinopathy, and retinal detachment generally are all retinal disorders that are difficult to treat with conventional therapies.
Age-related macular degeneration (AMD) is the major cause of severe visual loss in the United States for individuals over the age of 60. AMD occurs in either an atrophic or less commonly an exudative form. The atrophic form of AMD is also called “dry AMD,” and the exudative form of AMD is also called “wet AMD.”
In exudative AMD, blood vessels grow from the choriocapillaris through defects in Bruch's membrane, and in some cases the underlying retinal pigment epithelium. Organization of serous or hemorrhagic exudates escaping from these vessels results in fibrovascular scarring of the macular region with attendant degeneration of the neuroretina, detachment and tears of the retinal pigment epithelium, vitreous hemorrhage and permanent loss of central vision. This process is responsible for more than 80% of cases of significant visual loss in subjects with AMD. Currently there is no optimal treatment for wet AMD. Current or forthcoming treatments include laser photocoagulation, photodynamic therapy, treatment with pegylated aptamers, and treatment with certain small molecule agents.
Several studies have recently described the use of laser photocoagulation in the treatment of initial or recurrent neovascular lesions associated with AMD (Macular Photocoagulation Study Groups (1991) in Arch. Ophthal. 109:1220; Arch. Ophthal. 109:1232; Arch. Ophthal. 109:1242). Unfortunately, AMD subjects with subfoveal lesions subjected to laser treatment experienced a rather precipitous reduction in visual acuity (mean 3 lines) at 3 months follow-up. Moreover, at two years post-treatment treated eyes had only marginally better visual acuity than their untreated counterparts (means of 20/320 and 20/400, respectively). Another drawback of the procedure is that vision after surgery is immediately worse.
Photodynamic therapy (PDT) is a form of phototherapy, a term encompassing all treatments that use light to produce a beneficial reaction in a subject. Optimally, PDT destroys unwanted tissue while sparing normal tissue. Typically, a compound called a photosensitizer is administered to the subject. Usually, the photosensitizer alone has little or no effect on the subject. When light, often from a laser, is directed onto a tissue containing the photosensitizer, the photosensitizer is activated and begins destroying targeted tissue. Because the light provided to the subject is confined to a particularly targeted area, PDT can be used to selectively target abnormal tissue, thus sparing surrounding healthy tissue. PDT is currently used to treat retinal diseases such as AMD. PDT is currently the mainstay of treatment for subfoveal choroidal neovascularization in subjects with AMD (Photodynamic Therapy for Subfoveal Choroidal Neovascularization in Age Related Macular Degeneration with Verteporfin (TAP Study Group) Arch Ophthalmol. 1999 117:1329-1345.
Choroidal neovascularization (CNV) has proven recalcitrant to treatment in most cases. Conventional laser treatment can ablate CNV and help to preserve vision in selected cases not involving the center of the retina, but this is limited to only about 10% of the cases. Unfortunately, even with successful conventional laser photocoagulation, the neovascularization recurs in about 50-70% of eyes (50% over 3 years and >60% at 5 years). (Macular Photocoagulation Study Group, Arch. Ophthalmol. 204:694-701 (1986)). In addition, many subjects who develop CNV are not good candidates for laser therapy because the CNV is too large for laser treatment, or the location cannot be determined so that the physician cannot accurately aim the laser. Photodynamic therapy, although utilized in up to 50% of new cases of subfoveal CNV has only marginal benefits over natural history, and generally delays progression of visual loss rather than improving vision which is already decreased secondary to the subfoveal lesion. PDT is neither preventive or definitive. Several PDT treatments are usually required per subject and additionally, certain subtypes of CNV fare less well than others.
Although there is currently some off label use of intravitreal triamcinolone acetate, there are no other widely accepted therapies for subfoveal CNV. (Combined photodynamic Therapy with Verteporfin and Intravitreal Triamcinolone Acetonide for Choroidal Neovascularization. Ophthalmol 2003: 110:1517-1525).
Thus, there remains a long-felt need for methods, compositions, and devices that may be used to optimally prevent or significantly inhibit choroidal neovascularization and to prevent and treat wet AMD.
In addition to AMD, choroidal neovascularization is associated with such retinal disorders as presumed ocular histoplasmosis syndrome, myopic degeneration, angioid streaks, idiopathic central serous chorioretinopathy, inflammatory conditions of the retina and or choroid, and ocular trauma. Angiogenic damage associated with neovascularization occurs in a wide range of disorders including diabetic retinopathy, venous occlusions, sickle cell retinopathy, retinopathy of prematurity, retinal detachment, ocular ischemia and trauma.
Uveitis is another retinal disorder that has proven difficult to treat using existing therapies. Uveitis is a general term that indicates an inflammation of any component of the uveal tract. The uveal tract of the eye consists of the iris, ciliary body, and choroid. Inflammation of the overlying retina, called retinitis, or of the optic nerve, called optic neuritis, may occur with or without accompanying uveitis.
Uveitis is most commonly classified anatomically as anterior, intermediate, posterior, or diffuse. Posterior uveitis signifies any of a number of forms of retinitis, choroiditis, or optic neuritis. Diffuse uveitis implies inflammation involving all parts of the eye, including anterior, intermediate, and posterior structures.
The symptoms and signs of uveitis may be subtle, and vary considerably depending on the site and severity of the inflammation. Regarding posterior uveitis, the most common symptoms include the presence of floaters and decreased vision. Cells in the vitreous humor, white or yellow-white lesions in the retina and/or underlying choroid, exudative retinal detachments, retinal vasculitis, and optic nerve edema may also be present in a subject suffering from posterior uveitis.
Ocular complications of uveitis may produce profound and irreversible loss of vision, especially when unrecognized or treated improperly. The most frequent complications of posterior uveitis include retinal detachment; neovascularization of the retina, optic nerve, or iris; and cystoid macular edema.
Macular edema (ME) can occur if the swelling, leaking, and hard exudates noted in background diabetic retinopathy (BDR) occur within the macula, the central 5% of the retina most critical to vision. Background diabetic retinopathy (BDR) typically consists of retinal microaneurisms that result from changes in the retinal microcirculation. These microaneurisms are usually the earliest visible change in retinopathy seen on exam with an ophthalmoscope as scattered red spots in the retina where tiny, weakened blood vessels have ballooned out. The ocular findings in background diabetic retinopathy progress to cotton wool spots, intraretinal hemorrhages, leakage of fluid from the retinal capillaries, and retinal exudates. The increased vascular permeability is also related to elevated levels of local growth factors such as vascular endothelial growth factor. The macula is rich in cones, the nerve endings that detect color and upon which daytime vision depends. When increased retinal capillary permeability effects the macula, blurring occurs in the middle or just to the side of the central visual field, rather like looking through cellophane. Visual loss may progress over a period of months, and can be very annoying because of the inability to focus clearly. ME is a common cause of severe visual impairment.
As described above, treatment for CNV and other retinoproliferative conditions is primarily with laser photocoagulation. There have been many attempts, however, to treat these and other conditions such as macular edema and chronic inflammation with pharmaceuticals. For example, use of rapamycin to inhibit CNV and wet AMD has been described in U.S. application Ser. No. 10/665,203, which is incorporated herein by reference in its entirety. There are no approved medicines for CNV or proliferative retinopathy, but there is a great need for such a therapy, and the use of rapamycin to treat inflammatory diseases of the eye has been described in U.S. Pat. No. 5,387,589, titled Method of Treating Ocular Inflammation, with inventor Prassad Kulkarni, assigned to University of Louisville Research Foundation, the contents of which is incorporated herein in its entirety.
There are currently no approved devices to deliver therapeutic agents to the posterior segment of the eye from a location external to the eye. Likewise, except for steroid formulations, no therapeutic agents are delivered to the posterior segment from external injection sites with long acting delivery profiles. Particularly for chronic diseases, including those described herein, there is a great need for long acting methods for delivering active compounds to the posterior segment to treat CNV in such diseases as AMD, macular edema, proliferative retinopathies, and chronic inflammation.
Direct delivery of therapeutic agents to the eye as opposed to systemic administration is advantageous because the therapeutic agent concentration at the site of action is increased relative to the therapeutic agent concentration in a subject's circulatory system. Additionally, therapeutic agents are likely to have undesirable side effects when delivered systemically to treat posterior segment disease. Thus, localized drug delivery promotes efficacy while decreasing side effects and systemic toxicity.
Direct delivery can be achieved by placing the therapeutic agent directly into the interior of the eye, usually by injection, or can be achieved by delivering the therapeutic agent from a position external to the eye. One example of such external placement is delivery of a therapeutic agent by transscleral delivery. In transscleral delivery, a composition or device containing the therapeutic agent is placed outside of the sclera and the therapeutic agent diffuses across the sclera towards the interior of the eye. Direct placement of the therapeutic agent into the interior of the eye usually requires invasive placement procedures. In contrast, placement of the therapeutic agent external to the eye can be achieved much more easily. An additional advantage of external placement of a composition or device containing a therapeutic agent is that the device or composition is not present in the interior of the eye for extended periods of time. Interior placement, however, will result in a composition or device being present in the interior of the eye, which may have adverse effects on the proper functioning of the eye. For these reasons, external delivery is often to be preferred over direct delivery to the interior of the eye.
Although transscleral delivery of therapeutic agents to the eye is advantageous, there are many difficulties in developing such delivery mechanisms. The delivery system, whether it is a composition or device, will need to be of small size to enable placement of the composition or device in the ocular region close to the sclera. The delivery system will have to be large enough, however, to contain amounts of the therapeutic agent capable of delivering therapeutically effective amounts of the agent. If delivery of the therapeutic agent is needed for an extended period of time, the composition or device must be able to contain enough therapeutic agent to deliver therapeutic amounts for the extended period and must be able to remain in position for the extended period of time to allow extended delivery of the therapeutic agent. The delivery system may also need to minimize delivery to other tissues in the vicinity and concentrate delivery towards the interior of the eye.